Peripheral IV Insulin Infusion Infiltration Presenting as "Insulin Resistance".

OBJECTIVES: We present the case of a 66-year-old woman who developed hypoglycemia following the prolonged infiltration of a high dose continuous peripheral IV insulin infusion. STUDY SELECTION: Case report. DATA SOURCES AND EXTRACTION: PubMed was searched for relevant literature on exogenous hyperinsulinemic hypoglycemia. DATA SYNTHESIS: The patient was postlung transplantation and was receiving high doses of glucocorticoids. Despite increasing the peripheral IV insulin rate, hyperglycemia persisted. We discovered that the IV insulin infusion line infiltrated, resulting in a large subcutaneous insulin depot, estimated to be 450 units of regular insulin. She subsequently experienced prolonged hypoglycemia that was managed with concentrated dextrose containing fluids. In our literature search, there were no similar case reports. The literature on insulin overdose, usually from suicide attempts, can help guide the management of iatrogenic hyperinsulinemic hypoglycemia. Important management considerations include anticipated duration of hypoglycemia, supplemental glucose, fluid management, and electrolyte monitoring. CONCLUSION: Peripheral IV insulin infusion infiltration should be considered when patients do not respond to increasing rates of insulin infusion.

THE SIGNIFICANCE OF THYROGLOBULIN ANTIBODIES IN PAPILLARY THYROID CANCER.

ABBREVIATIONS: CLT = chronic lymphocytic thyroiditis PTC = papillary thyroid cancer TgAb = thyroglobulin antibodies.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY POSITION STATEMENT ON THYROID DYSFUNCTION CASE FINDING.

Hypothyroidism and hyperthyroidism can be readily diagnosed and can be treated in a safe, cost-effective manner. Professional organizations have given guidance on how and when to employ thyroid-stimulating hormone testing for the detection of thyroid dysfunction. Most recently, the United States Preventive Services Task Force did not endorse screening for thyroid dysfunction based on a lack of proven benefit and potential harm of treating those with thyroid dysfunction, which is mostly subclinical disease. The American Association of Clinical Endocrinologists (AACE) is concerned that this may discourage physicians from testing for thyroid dysfunction when clinically appropriate. Given the lack of specificity of thyroid-associated symptoms, the appropriate diagnosis of thyroid disease requires biochemical confirmation. The Thyroid Scientific Committee of the AACE has produced this White Paper to highlight the important difference between screening and case-based testing in the practice of clinical medicine. We recommend that thyroid dysfunction should be frequently considered as a potential etiology for many of the nonspecific complaints that physicians face daily. The application and success of safe and effective interventions are dependent on an accurate diagnosis. We, therefore, advocate for an aggressive case-finding approach, based on identifying those persons most likely to have thyroid disease that will benefit from its treatment.

AACE/ACE disease state commentary: molecular diagnostic testing of thyroid nodules with indeterminate cytopathology.

• Approximately 10 to 25% of fine-needle aspiration (FNA) biopsies yield an indeterminate result often labeled as atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) or follicular neoplasm/suspicious for follicular neoplasm (FN/SFN). The risk of malignancy typically varies between 15 and 30% for these categories. • Although many markers are in development and have been studied in a research setting, 2 principal tests are currently marketed for use to improve the malignancy risk assessment of "indeterminate" thyroid nodules. "Rule In" and "Rule Out" tests attempt to confirm or exclude the presence of cancer within a thyroid nodule by means of robust positive (PPV) or negative predictive values (NPV), respectively. • The Rule In tests determine the presence of single gene point mutations (BRAFV600E or RAS) or gene rearrangements (RET/PTC, PAX8/PPARγ) that have been shown to increase the ability to predict cancer, while the Rule Out test (Afirma® gene expression classifier, GEC) utilizes a proprietary gene expression classifier (RNA expression) specifically designed to maximize the ability to define a process as benign. • Among the presently available tests, only the BRAFV600E and RET/PTC rearrangement are associated with a PPV that approaches 100%. • The category of cytologically "indeterminate" nodule (AUS/FLUS, FN/SFN), cytopathology practice patterns, and the prevalence of malignancy within the population being tested all impact the NPVs and PPVs for the tests in question. • At present, molecular testing is meant to complement and not replace clinical judgment, sonographic assessment, and visual cytopathology interpretation. • As molecular testing is new and advances in the field are regularly occurring, clinicians need to stay informed, as recommendations for use within practice are expected to evolve.

Acute liver failure with thyrotoxicosis treated with liver transplantation.

OBJECTIVE: We describe a young woman with previously undiagnosed thyrotoxicosis who presented with acute liver failure (ALF). METHODS: We present a case report and review the relevant literature. RESULTS: An extensive evaluation excluded possible causes of ALF other than thyrotoxicosis. The management of thyrotoxicosis posed several unique challenges in the setting of ALF, particularly because we did not want to use potentially hepatotoxic thionamides. The patient was treated with prednisone and propranolol and was started on potassium iodide when she was listed for liver transplantation. She underwent an uncomplicated liver transplant and subsequent thyroidectomy and is doing well. CONCLUSION: This well-characterized case describes thyrotoxicosis as a possible cause of ALF after thoroughly excluding other possible causes and illustrates the challenges of simultaneously managing both disorders. To our knowledge, this is the first report of ALF possibly resulting from untreated thyrotoxicosis that was successfully treated with liver transplantation.

Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association.

OBJECTIVE: Hypothyroidism has multiple etiologies and manifestations. Appropriate treatment requires an accurate diagnosis and is influenced by coexisting medical conditions. This paper describes evidence-based clinical guidelines for the clinical management of hypothyroidism in ambulatory patients. METHODS: The development of these guidelines was commissioned by the American Association of Clinical Endocrinologists (AACE) in association with American Thyroid Association (ATA). AACE and the ATA assembled a task force of expert clinicians who authored this article. The authors examined relevant literature and took an evidence-based medicine approach that incorporated their knowledge and experience to develop a series of specific recommendations and the rationale for these recommendations. The strength of the recommendations and the quality of evidence supporting each was rated according to the approach outlined in the American Association of Clinical Endocrinologists Protocol for Standardized Production of Clinical Guidelines-2010 update. RESULTS: Topics addressed include the etiology, epidemiology, clinical and laboratory evaluation, management, and consequences of hypothyroidism. Screening, treatment of subclinical hypothyroidism, pregnancy, and areas for future research are also covered. CONCLUSIONS: Fifty-two evidence-based recommendations and subrecommendations were developed to aid in the care of patients with hypothyroidism and to share what the authors believe is current, rational, and optimal medical practice for the diagnosis and care of hypothyroidism. A serum thyrotropin is the single best screening test for primary thyroid dysfunction for the vast majority of outpatient clinical situations. The standard treatment is replacement with L-thyroxine. The decision to treat subclinical hypothyroidism when the serum thyrotropin is less than 10 mIU/L should be tailored to the individual patient.

Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association.

BACKGROUND: Hypothyroidism has multiple etiologies and manifestations. Appropriate treatment requires an accurate diagnosis and is influenced by coexisting medical conditions. This paper describes evidence-based clinical guidelines for the clinical management of hypothyroidism in ambulatory patients. METHODS: The development of these guidelines was commissioned by the American Association of Clinical Endocrinologists (AACE) in association with American Thyroid Association (ATA). AACE and the ATA assembled a task force of expert clinicians who authored this article. The authors examined relevant literature and took an evidence-based medicine approach that incorporated their knowledge and experience to develop a series of specific recommendations and the rationale for these recommendations. The strength of the recommendations and the quality of evidence supporting each was rated according to the approach outlined in the American Association of Clinical Endocrinologists Protocol for Standardized Production of Clinical Guidelines-2010 update. RESULTS: Topics addressed include the etiology, epidemiology, clinical and laboratory evaluation, management, and consequences of hypothyroidism. Screening, treatment of subclinical hypothyroidism, pregnancy, and areas for future research are also covered. CONCLUSIONS: Fifty-two evidence-based recommendations and subrecommendations were developed to aid in the care of patients with hypothyroidism and to share what the authors believe is current, rational, and optimal medical practice for the diagnosis and care of hypothyroidism. A serum thyrotropin is the single best screening test for primary thyroid dysfunction for the vast majority of outpatient clinical situations. The standard treatment is replacement with L-thyroxine. The decision to treat subclinical hypothyroidism when the serum thyrotropin is less than 10 mIU/L should be tailored to the individual patient.

Metastatic papillary thyroid cancer misdiagnosed as non-small [corrected] cell lung cancer.

BACKGROUND: Thyroid and lung cancers, two malignancies with similar immunohistological characteristics, have vastly different biologic behaviors and treatment approaches. As thyroid cancers commonly spread to the lungs, metastatic thyroid cancer should be included in the differential diagnosis of a pulmonary lesion or lesions. SUMMARY: A 54-year-old woman with a remote history of stage IV nonsmall cell lung cancer was found to have FDG avidity in the thyroid and right cervical lymph nodes. Subsequent ultrasonographic findings and FNA cytology led to a total thyroidectomy, bilateral central lymphadenectomy, and right modified radical lymph node dissection for primary thyroid cancer. Reviews and comparisons of the pulmonary and cervical surgical specimens revealed that the patient had been misdiagnosed for the previous 6 years; she had metastatic papillary thyroid cancer to the lung. The patient's original diagnosis of stage IV lung cancer was based upon the original lung biopsy showing positive thyroid transcription factor-1 (TTF-1) immunostaining. The original diagnosis was questioned because of her long survival when she was diagnosed with locally advanced papillary thyroid cancer. Further analyses of the immunohistological characteristics of both surgical specimens--including staining for TTF-1, thyroglobulin, CD57, S-100, and CEA--documented the correct diagnosis. CONCLUSIONS: A thorough understanding of the natural history and surgical pathology, including immunohistology, of lung and thyroid cancers is necessary for a correct and timely diagnosis and appropriate treatment. Because TTF-1 expression is seen in both thyroid and lung cancers, careful consideration should be given to both malignancies when evaluating patients with thyroid and pulmonary nodules.

Results of rosiglitazone therapy in patients with thyroglobulin-positive and radioiodine-negative advanced differentiated thyroid cancer.

BACKGROUND: Rosiglitazone is a peroxisome proliferator-activated receptor (PPAR) gamma agonist that has shown promise as both an antiproliferative and redifferentiating agent for the treatment of thyroid cancer in preclinical studies. We investigated the efficacy and side effects of rosiglitazone therapy in patients with differentiated thyroid cancer of follicular cell origin that fails to take up radioiodine or is unresectable. METHODS: Twenty patients with differentiated thyroid cancer were enrolled in an open-label, phase II trial of oral rosiglitazone treatment (4 mg daily for 1 week, then 8 mg daily for 7 weeks). RESULTS: Five of 20 patients had a positive radioiodine scan after rosiglitazone treatment. Four patients had radioiodine uptake in the neck and one patient had uptake in the pelvis. Unstimulated thyroglobulin levels after rosiglitazone treatment increased in five patients, remained stable in 12 patients, and decreased in three patients. Seven patients had progressive disease on follow-up cross-sectional imaging; six patients in the size and number of lung metastasis and two patients in the size of the neck tumors. Overall, five patients had a partial response (decreased thyroglobulin or positive radioiodine uptake), three patients had stable disease (no change in thyroglobulin and radioiodine uptake status), and 12 patients had disease progression (increased thyroglobulin). By RECIST criteria, no patient had a complete or partial response to rosiglitazone treatment at 3 months follow-up. The mean follow-up time after protocol treatment was 12 months (median 12 months). CONCLUSIONS: Our findings suggest that rosiglitazone therapy may induce radioiodine uptake and reduce serum thyroglobulin levels in some patients with differentiated thyroid cancer but this did not result in clinically significant response on long-term follow-up. Moreover, no patients had response to rosiglitazone therapy by anatomic imaging studies.

Graves ophthalmopathy after radiation treatment of thyroid cancer.

OBJECTIVE: To describe a patient with metastatic thyroid cancer who developed Graves ophthalmopathy after treatment with radioiodine (I 131) and external beam radiation. METHODS: We present a case report that includes clinical, laboratory, and radiologic findings and a brief review of the literature. RESULTS: A 49-year-old woman who had had a total thyroidectomy and neck dissection followed by I 131 treatment 5 years earlier for papillary thyroid cancer presented for follow-up management after recent neck dissection for recurrent disease. Because she had thyroglobulin antibodies, she was again treated with I 131 after preparation with recombinant human thyroid-stimulating hormone. A post-treatment scan revealed uptake in the right iliac crest. A fludeoxyglucose F 18 positron emission tomography/computed tomography fusion scan revealed osseous metastases in the right pelvis, and external beam radiotherapy was delivered to this area. Approximately 5 months later, she developed periocular swelling and excessive tearing. Magnetic resonance imaging of the orbits revealed enlargement of the extraocular muscles. Serum thyroid-stimulating immunoglobulins were greatly elevated. CONCLUSION: This case corroborates an earlier report to suggest that radiation-associated thyroid injury in a patient with thyroid cancer may be followed by Graves ophthalmopathy and appearance of thyroid-stimulating immunoglobulins in the serum.

A phase II trial of rosiglitazone in patients with thyroglobulin-positive and radioiodine-negative differentiated thyroid cancer.

BACKGROUND: Rosiglitazone is a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist that has been shown to induce differentiation, cell cycle arrest, and apoptosis in a variety of human cancers including thyroid cancer. METHODS: Ten patients with differentiated thyroid cancer were enrolled in an open-label, phase II trial of oral rosiglitazone treatment (4 mg daily for 1 week, then 8 mg daily for 7 weeks). The levels of PPARgamma receptor mRNA and protein expression were determined in the patient's neoplasm. RESULTS: Of 10 patients, 4 had positive radioiodine scans after rosiglitazone therapy with uptake in the neck in 3 patients and in the pelvis in 1 patient. After treatment, the serum thyroglobulin level decreased in 2 patients, increased in 5 patients, and was stable in 3 patients. No patient developed clinically important toxicity associated with rosiglitazone treatment. We found no relationship in the level of PPARgamma mRNA and protein expression in patients who had radioiodine uptake compared with those who did not. CONCLUSIONS: Our findings suggest that rosiglitazone treatment may induce radioiodine uptake in some patients with thyroglobulin-positive and radioiodine-negative differentiated thyroid cancer. We found no relationship between the expression level of the PPARgamma mRNA and protein in the neoplasm and radioiodine uptake status after rosiglitazone therapy, questioning the potential pathway of effect.

Triiodothyronine production in Graves' hyperthyroidism.

OBJECTIVE: To quantify the relative contributions of thyroid secretion and peripheral generation to triiodothyronine (T(3)) production in untreated Graves' hyperthyroidism. PATIENTS, DESIGN, AND MEASUREMENTS: Thirty-one patients with hyperthyroidism, of whom 6 had T(3) toxicosis, and 21 surgically and radioiodine ablated patients with thyroid cancer on thyroid stimulating hormone-suppressive therapy in whom serum T(3) should reflect peripheral generation alone were compared with respect to serum free thyroxine (T(4)) and serum free T(3) concentrations. MAIN OUTCOMES: Serum free T(4)/free T(3) molar ratios were virtually identical in the patients with T(4)+T(3) toxicosis (2.7 +/- 0.4) and those with T(3) toxicosis (2.6 +/- 0.4) and were significantly lower than in the patients with thyroid cancer (4.0 +/- 0.4) (p < 0.001). In the hyperthyroid patients, peripherally generated T(3) was calculated as the quotient of the individual serum free T(4) concentration and the free T(4)/free T(3) molar ratio in thyroid cancer; this value was subtracted from the individual measured free T(3) concentration to derive the value for secreted T3. Secreted T(3) accounted for 33 +/- 6% of T(3) production in T(4)+T(3) toxicosis and 34 +/- 10% in T(3) toxicosis. CONCLUSIONS: This study indicates that about one third of T3 production in untreated Graves' hyperthyroidism, irrespective of whether presenting as T4+T3 toxicosis or T3 toxicosis, arises from thyroid secretion as compared to about 20% in normal individuals.

Observations concerning the natural history of subclinical hyperthyroidism.

OBJECTIVE: To examine the natural history of a subnormal serum thyroid-stimulating hormone (TSH) concentration with normal concentrations of both serum free thyroxine (FT4) and free triiodothyronine (FT3) (subclinical hyperthyroidism). PATIENTS, DESIGN, AND MEASUREMENTS: A retrospective analysis was undertaken and yielded 16 ambulatory patients who had presented with subclinical hyperthyroidism and were longitudinally followed with measurements of serum TSH and both FT4 and FT3 for a cumulative follow-up of 11 to 36 months. Seven of the patients had subclinical Graves' hyperthyroidism as judged from the presence of thyroid-stimulating immunoglobulins (TSI) in serum, and 9 had multinodular goiter confirmed with ultrasound and no TSI. RESULTS: In the 7 patients with TSI, serum TSH reverted to normal in 5 patients, with disappearance or decrease of TSI in 4, within 3 to 19 months. In 1 patient, subnormal serum TSH accompanied by both normal FT4 and FT3 has persisted for 15 months, and in a second patient serum TSH reverted to normal within 9 months, but at follow-up 27 months later overt hyperthyroidism had emerged. In the 9 patients with multinodular goiter, subnormal serum TSH accompanied by both normal FT4 and FT3 persisted during cumulative follow-up that ranged from 11 to 36 months. CONCLUSIONS: This study suggests that the natural history of subclinical hyperthyroidism is variable, resolving or occasionally evolving in subclinical Graves' disease and persisting unchanged in multinodular goiter.

Extent of disease and practice patterns for medullary thyroid cancer.

BACKGROUND: There have been significant improvements in the management of medullary thyroid cancer (MTC), and consensus treatment guidelines have been established by numerous international and national societies. It is unclear if the advances in diagnosis and treatment of MTC have led to earlier diagnosis and more complete initial treatment of patients with MTC. STUDY DESIGN: Patients with MTC (n=1,070) were identified in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database from 12 population-based cancer registries between 1973 and 2000. Four equal-time quartiles (group I=1973 to 1979, group II=1980 to 1986, group III=1987 to 1993, and group IV=1994 to 2000) were compared for changes in demographics, extent of disease, and treatment. RESULTS: Mean tumor size was significantly larger in 1988 than in 1989 through 2000 (p=0.044), but there was no significant trend toward smaller tumor size. The number of patients having total or near total thyroidectomy increased significantly in the latter two quartiles (p < 0.001) but not the number of patients having cervical lymph node dissection. Unfortunately, 15% of patients in group IV still had less than total or near total thyroidectomy, and 41% had no cervical lymph node dissection. There were no significant differences in age, gender, rate of lymph node or distant metastasis, SEER stage, TNM stage, and cause-specific mortality among the four time groups and annually. CONCLUSIONS: There was no significant trend toward earlier stage of disease at diagnosis and treatment and no significant increase in the survival of patients with MTC during a 28-year period. A high proportion of patients continue to receive less than optimal initial surgical treatment.

Anaplastic thyroid carcinoma. Treatment outcome and prognostic factors.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is rare but is one of the most aggressive human malignancies. Several prognostic factors have been observed in patients with ATC, and some experts advocate aggressive multimodal therapy in selected patients. However, it is unclear whether such an approach significantly improves survival. The authors analyzed prognostic factors and treatment outcomes in patients with ATC reported in the National Cancer Institute's Surveillance, Epidemiology, and End Results data base. METHODS: The cohort consisted of 516 patients with ATC reported to 12 population-based cancer registries between 1973 and 2000. Demographic, pathologic, and treatment data were used for univariate and multivariate survival analyses. RESULTS: The mean patient age at diagnosis was 71.3 years, and there were 171 men and 345 women. Eight percent of patients had intrathyroidal tumors, 38% had extrathyroidal tumors and/or lymph node invasion, and 43% of patients had distant metastasis. The average tumor size was 6.4 cm (range, 1-15 cm). Sixty-four percent of patients underwent surgical resection of their primary tumor, and 63% received external beam radiotherapy. The overall cause-specific mortality rate was 68.4% at 6 months and 80.7% at 12 months. Univariate analysis showed that age < 60 years, female gender, intrathyroidal tumor, external beam radiotherapy, surgical resection, and combined surgical resection of tumor and radiotherapy were associated with a lower cause-specific mortality. On multivariate analysis, only age < 60 years, an intrathyroidal tumor, and the combined use of surgical and external beam radiation therapy were identified as independent predictors of lower cause-specific mortality. CONCLUSIONS: Although most patients with ATC had an extremely poor prognosis, patients < 60 years old with intrathyroidal tumors survived longer. Surgical resection with external beam radiotherapy for ATC was associated with lower cause-specific mortality.

Evaluation of a "formal" endocrinology curbside consultation service: advice by means of internet, fax, and telephone.

OBJECTIVE: To describe the development, implementation, and assessment of an Internet- and fax-based endocrinology curbside consultation service. METHODS: An Internet- and fax-based endocrinology consultation service was designed by developing a simple Web site so that requesting physicians could complete a form about the patient. Community and academic-based primary-care physicians were invited to use the service. One month after each consultation, a follow-up questionnaire about the effectiveness and use of the Internet and fax consultation service was sent to each physician who had requested the consultation. RESULTS: During the 5-month period in which the service was offered, 67 physicians requested a total of 85 "formal" endocrinology curbside consultations. Of these 85 requests, 46 were by e-mail, 31 by fax, and 8 by telephone. Follow-up questionnaires were returned by 61 of the 67 physicians who used the service. One hundred percent of the physicians found the service to be useful, and about 33% noted formal consultation had been avoided. In approximately 55% of the consultations, physicians indicated that the response caused them to alter the treatment of their patient. Consultation questions encompassed the full spectrum of endocrinology. The issues were approximately equally distributed among test interpretation, medication, and management. CONCLUSION: We successfully designed and implemented an Internet- and fax-based endocrinology curbside consultation service. This form of consultation was used by physicians and brought about change in the management of their patients.